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Role of integrin-?3 protein in macrophage polarization and regeneration of injured muscle.

ABSTRACT: Following injury, skeletal muscle achieves repair by a highly coordinated, dynamic process resulting from interplay among numerous inflammatory, growth factors and myogenic regulators. To identify genes involved in muscle regeneration, we used a microarray analysis; there was a significant increase in the expression of a group of integrin genes. To verify these results, we used RT-PCR and Western blotting and found that 12 integrins were up-regulated from 3 h to 15 days following injury. Following muscle injury, integrin-?3 was initially expressed, mainly in macrophages. In integrin-?3 global KO mice, the expression of myogenic genes was decreased and muscle regeneration was impaired, whereas fibrosis was enhanced versus events in wild type (WT) mice. The mechanism for these responses in integrin-?3 KO mice included an infiltration of macrophages that were polarized into the M2 phenotype. These macrophages produced more TGF-?1 and increased TGF-?1/Smad signaling. In vitro, we confirmed that M2 macrophages lacking integrin-?3 produced more TGF-?1. Furthermore, transplantation of bone marrow cells from integrin-?3 KO mice into WT mice led to suppression of the infiltration and accumulation of macrophages into injured muscles. There was also impaired muscle regeneration with an increase in muscle fibrosis. Our results demonstrate that integrin-?3 plays a fundamental role in muscle regeneration through a regulation of macrophage infiltration and polarization leading to suppressed TGF-?1 production. This promotes efficient muscle regeneration. Thus, an improvement in integrin-?3 function could stimulate muscle regeneration.

SUBMITTER: Zhang L

PROVIDER: S-EPMC3307266 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Role of integrin-β3 protein in macrophage polarization and regeneration of injured muscle.

Zhang Liping L Dong Yanjun Y Dong Yanlan Y Cheng Jizhong J Du Jie J

The Journal of biological chemistry 20111230 9

Following injury, skeletal muscle achieves repair by a highly coordinated, dynamic process resulting from interplay among numerous inflammatory, growth factors and myogenic regulators. To identify genes involved in muscle regeneration, we used a microarray analysis; there was a significant increase in the expression of a group of integrin genes. To verify these results, we used RT-PCR and Western blotting and found that 12 integrins were up-regulated from 3 h to 15 days following injury. Followi ...[more]

PMID: 22210777

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Project description:BackgroundInjection of exogenous mitochondria has been shown to improve the ischaemia-damaged myocardium, but the effect of mitochondrial transplant therapy (MTT) to restore skeletal muscle mass and function has not been tested following neuromuscular injury. Therefore, we tested the hypothesis that MTT would improve the restoration of muscle function after injury.MethodsBaCl2 was injected into the gastrocnemius muscle of one limb of 8-12-week-old C57BL/6 mice to induce damage without injury to the resident stem cells. The contralateral gastrocnemius muscle was injected with phosphate-buffered saline (PBS) and served as the non-injured intra-animal control. Mitochondria were isolated from donor mice. Donor mitochondria were suspended in PBS or PBS without mitochondria (sham treatment) and injected into the tail vein of BaCl2 injured mice 24 h after the initial injury. Muscle repair was examined 7, 14 and 21 days after injury.ResultsMTT did not increase systemic inflammation in mice. Muscle mass 7 days following injury was 21.9 ± 2.1% and 17.4 ± 1.9% lower (P < 0.05) in injured as compared with non-injured intra-animal control muscles in phosphate-buffered saline (PBS)- and MTT-treated animals, respectively. Maximal plantar flexor muscle force was significantly lower in injured as compared with uninjured muscles of PBS-treated (-43.4 ± 4.2%, P < 0.05) and MTT-treated mice (-47.7 ± 7.3%, P < 0.05), but the reduction in force was not different between the experimental groups. The percentage of collagen and other non-contractile tissue in histological muscle cross sections, was significantly greater in injured muscles of PBS-treated mice (33.2 ± 0.2%) compared with MTT-treated mice (26.5 ± 0.2%) 7 days after injury. Muscle wet weight and maximal muscle force from injured MTT-treated mice had recovered to control levels by 14 days after the injury. However, muscle mass and force had not improved in PBS-treated animals by 14 days after injury. The non-contractile composition of the gastrocnemius muscle tissue cross sections was not different between control, repaired PBS-treated and repaired MTT-treated mice 14 days after injury. By 21 days following injury, PBS-treated mice had fully restored gastrocnemius muscle mass of the injured muscle to that of the uninjured muscle, although maximal plantar flexion force was still 19.4 ± 3.7% (P < 0.05) lower in injured/repaired gastrocnemius as compared with uninjured intra-animal control muscles.ConclusionsOur results suggest that systemic mitochondria delivery can enhance the rate of muscle regeneration and restoration of muscle function following injury.

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Role of integrin-?3 protein in macrophage polarization and regeneration of injured muscle.

Publications

Role of integrin-β3 protein in macrophage polarization and regeneration of injured muscle.

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